For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Black Box Warning

Qualitative and Quantitative Composition

RAMIPRES-1.25 Tablets

Each tablet contains……….Ramipril 1.25 mg

RAMIPRES-2.5 Tablets

Each tablet contains……….Ramipril 2.5 mg

RAMIPRES-5 Tablets

Each tablet contains……….Ramipril 5 mg

RAMIPRES-10 Tablets

Each tablet contains……….Ramipril 10 mg

Dosage Form(s) and Strength(s)

Tablet containing 1.25 mg, 2.5 mg, 5 mg and 10 mg of ramipril.

Clinical Particulars

Therapeutic Indications

Hypertension

RAMIPRES is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using Ramipril, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that Ramipril does not have a similar risk.

In considering use of Ramipril, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients.

Reduction in Risk of Myocardial Infarction, Stroke and Death from Cardiovascular Causes

RAMIPRES is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes. Ramipril can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering therapy).

Heart Failure Post-myocardial Infarction

RAMIPRES is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of ramipril to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure.

Posology and Method of Administration

Blood pressure decreases associated with any dose of ramipril depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, the initial starting dose should be 1.25 mg once daily.

Hypertension

The recommended initial dose for patients to be treated for hypertension, not receiving a diuretic is 2.5 mg once a day. Dosage should be adjusted according to the blood pressure response. The usual maintenance dosage range is 2.5 to 20 mg/day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with ramipril alone, a diuretic can be added.

Reduction in Risk of Myocardial Infarction, Stroke and Death from Cardiovascular Causes

RAMIPRES should be given at an initial dose of 2.5 mg, once a day for 1 week, 5 mg once a day for the next 3 weeks and then increased as tolerated, to a maintenance dose of 10 mg once daily. If the patient is hypertensive or recently post-myocardial infarction, it can be given as a divided dose.

Heart Failure Post-Myocardial Infarction

For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose is RAMIPRES-2.5 twice daily (5 mg daily). A patient who becomes hypotensive at this dose may be switched to RAMIPRES-1.25 twice daily. After one week at the starting dose, patients should be titrated (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.

After the initial dose of RAMIPRES, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, the dose of any concomitant diuretic should be reduced as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of RAMIPRES does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

The RAMIPRES tablet is usually swallowed whole.

Concomitant administration of RAMIPRES with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium.

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of RAMIPRES. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with RAMIPRES. Then, if blood pressure is not controlled with RAMIPRES alone, diuretic therapy should be resumed.

If the diuretic cannot be discontinued, an initial dose of 1.25 mg Ramipril should be used to avoid excess hypotension.

Dosage Adjustment in Renal Impairment

In patients with creatinine clearance <40 mL/min/1.73 m² (serum creatinine approximately >2.5 mg/dL) doses only 25% of those normally used should be expected to induce full therapeutic levels of ramiprilat.

Hypertension

For patients with hypertension and renal impairment, the recommended initial dose is RAMIPRES-1.25 once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.

Heart Failure Post Myocardial Infarction

For patients with heart failure and renal impairment, the recommended initial dose is RAMIPRES-1.25 once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability.

Contraindications

Ramipril tablets are contraindicated in patients who are hypersensitive to this product or any other angiotensin converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

Special Warnings and Precautions for Use

Anaphylactoid and Possibly Related Reactions

Presumably because drugs that act directly on the RAAS (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including ramipril) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with ramipril and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) should be promptly administered.

Intestinal Angioedema

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) of white patients. These rates were not different statistically.

Anaphylactoid Reactions during Desensitization

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions during Membrane Exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension

Ramipril can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Ramipril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with Ramipril.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, Ramipril therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of ramipril or diuretic is increased.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of physiological saline. Ramipril treatment usually can be continued following restoration of blood pressure and volume.

Hepatic Failure

Rarely, ACE inhibitors, including Ramipril, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hyponatremia

Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and subsequent hyponatremia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatremia.

Neutropenia and Agranulocytosis

As with other ACE inhibitors, rarely, a mild- in isolated cases severe- reduction in the red blood cell count and hemoglobin content, white blood cell or platelet count may develop. In isolated cases, agranulocytosis, pancytopenia and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen vascular disease (e.g. systemic lupus erythematosus, scleroderma) and renal impairment. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

Fetal Toxicity

Pregnancy

Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Ramipril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Ramipril, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Ramipril for hypotension, oliguria, and hyperkalemia.

No teratogenic effects of Ramipril (ramipril) were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

Congestive Heart Failure

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, ramipril therapy should be started under close medical supervision and follow the patients closely for the first 2 weeks of treatment and whenever the dose of ramipril or diuretic is increased.

Heart Failure Post-Myocardial Infarction

In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of ramipril. If the initial dose of 2.5 mg ramipril cannot be tolerated, use an initial dose of 1.25 mg ramipril to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.

Surgery and Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Ramipril should be discontinued where possible one day before surgery.

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including Ramipril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of Ramipril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Ramipril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Ramipril and/or discontinuation of the diuretic may be required.

Hyperkalemia

In clinical trials with ramipril, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ramipril. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Ramipril.

Cough

Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent non-productive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of ACE inhibitor induced-cough in the differential diagnosis of cough.

Impaired Liver Function

Since ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. However, since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/or ascites, particular caution should be exercised in treating these patients.

Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Dual Blockade of the Renin-Angiotensin System (RAAS)

Telmisartan

The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.

Drug Interactions

Nonsteroidal Anti-inflammatory Agents (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, reduce the starting dose.

Antihypertensive Agents and Other Substances that may Decrease Blood Pressure: Co-administration of ramipril with antihypertensive agents (e.g. diuretics) or with substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) may potentiate the risk of hypotension.

Agents Increasing Serum Potassium: Coadministration of ramipril with other drugs that raise serum potassium levels [potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin)] may result in hyperkalemia. Monitor serum potassium in such patients.

Other Agents Affecting RAAS: In general, avoid combined use of RAAS inhibitors. Do not co-administer aliskiren with ramipril in patients with diabetes.

With Potassium Supplements and Potassium-sparing Diuretics:

Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium, therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Gold:

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ramipril.

Other:

Neither Ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of Ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of Ramipril and warfarin did not adversely affect the anticoagulant effects of the latter drug. Additionally, co-administration of Ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects’ state of anti-coagulation.

Use in Special Population

Patients with Renal Impairment

As a consequence of inhibiting the RAAS, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the RAAS, treatment with ACE inhibitors, including ramipril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases are usually reversible upon discontinuation of ramipril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when ramipril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ramipril and/or discontinuation of the diuretic may be required.

A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of creatinine clearance: normal (>80 mL/min), mild impairment (40-80 mL/min), moderate impairment (15-40 mL/min), and severe impairment (<15 mL/min). On average, the AUC_0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted downward in patients with moderate-to-severe renal impairment.

Patients with Hepatic Impairment 

Rarely, ACE inhibitors, including ramipril, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue ramipril if patient develops jaundice or marked elevations of hepatic enzymes.

As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.

Lactating Women

Ingestion of a single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use ramipril in nursing mothers.

Paediatric Patients

Neonates with a History of in utero Exposure to Ramipril

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which crosses the placenta, can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.

Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.

Geriatric Patients

Of the total number of patients who received ramipril in U.S. clinical studies of ramipril, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.

Effects on Ability to Drive and Use Machines

You may feel dizzy while taking RAMIPRES tablets. This is more likely to happen when you start taking RAMIPRES tablets or start taking a higher dose. If this happens, do not drive or use any tools or machines.

Undesirable Effects

Hypertension

Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in ramipril patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with ramipril. The most common reasons for discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).

Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2%  vs. 1% , respectively).

Heart Failure Post-Myocardial Infarction

Adverse reactions (except laboratory abnormalities) considered possibly/ probably related to study drug that occurred in more than 1% of patients and more frequently on ramipril are shown below (table 2). The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study.

Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials.

Other Adverse Reactions

Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):

Body as a Whole:  Anaphylactoid reactions

Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials), syncope, and palpitations

Hematologic: Pancytopenia, hemolytic anemia, thrombocytopenia,

Renal: Acute renal failure, Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with a diuretic.

Angioneurotic Edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ramipril.

Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, taste disturbance

Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome.

Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.

Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive antinuclear antibody, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.

Other: Arthralgia., arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, and weight gain.

Post-marketing Experience

In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ramipril therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.

Clinical Laboratory Test Findings

Creatinine and Blood Urea Nitrogen

Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis. As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient’s serum potassium frequently.

Hemoglobin and Hematocrit

Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin or hematocrit.

Other (Causal Relationships Unknown)

Clinically important changes in standard laboratory tests were rarely associated with ramipril administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In U.S. trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.

Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

Pharmacological Properties 

Mechanism of Action

Ramipril and ramiprilat (the active metabolite of ramipril) inhibit angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ramipril alone for up to 56 weeks, approximately 4% of patients during the trial had abnormally high serum potassium and an increase from baseline more than 0.75 mEq/L, and none of the patients had abnormally low potassium and a decrease from baseline more than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ramipril and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or more, and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or more. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ramipril remains to be elucidated.

While the mechanism through which ramipril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system (RAAS), ramipril has an antihypertensive effect even in patients with low-renin hypertension. Although ramipril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-Black patients.

Pharmacodynamic Properties

Single doses of ramipril of 2.5-20 mg produce approximately 60-80% inhibition of ACE activity 4 hours after dosing with approximately 40-60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

Pharmacokinetic Properties

Absorption

Following oral administration of ramipril, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50-60% and is not significantly influenced by the presence of food in the gastrointestinal tract,

Distribution

Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2-4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 to 10 µg/ml.

Metabolism

Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites is eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5-20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.

Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2-4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9-18 hours. The terminal elimination phase has a prolonged half-life (more than 50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13-17 hours.

After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ramipril, especially at low doses (2.5 mg), but the difference is clinically insignificant.

In patients with creatinine clearance less than 40 mL/min/1.73m², peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3-4 times as large as it is in patients with normal renal function who receive similar doses.

In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.

Excretion

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m² had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.

Other Special Populations

Renal Impairment

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

Hepatic Impairment

In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed, due to diminished activity of hepatic esterases, and plasma ramipril levels in these patients were increased. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.

Pediatric Population

The pharmacokinetic profile of ramipril was studied in 30 pediatric hypertensive patients, aged 2-16 years, weighing >10 kg. After doses of 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Peak plasma concentrations of ramiprilat occurred within 23 hours. Ramiprilat clearance highly correlated with the log of body weight (p<0.01) as well as dose (p<0.001). Clearance and volume of distribution increased with increasing children age for each dose group.

The dose of 0.05 mg/kg in children achieved exposure levels comparable to those in adults treated with ramipril 5 mg. The dose of 0.2 mg/kg in children resulted in exposure levels higher than the maximum recommended dose of 10 mg per day in adults.

Non-Clinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

Description

Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.

Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl] octa hydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester. Its empirical formula is C₂₃H₃₂N₂O₅ and its molecular weight is 416.5.

The structural formula for ramipril is:

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf Life

24 months

Packaging Information

Ramipres-1.25: Strip of 10 tablets

Ramipres-2.5: Strip of 10 tablets

Ramipres-5: Strip of 10 tablets

Ramipres-10: Strip of 10 tablets

Storage and Handling Instruction

Do not store above 25˚ C.

Patient Counselling Information

1. What RAMIPRES tablets are and what they are used for?

RAMIPRES tablets contain the active ingredient ramipril. This belongs to a group of medicines called ACE inhibitors (Angiotensin Converting Enzyme Inhibitors).

RAMIPRES tablets work by:

• decreasing your body’s production of substances that could raise your blood pressure
• making your blood vessels relax and widen
• making it easier for your heart to pump blood around your body.

RAMIPRES tablets are used:

• to treat high blood pressure (hypertension)
• to reduce the risk or delay the worsening of kidney problems (whether or not you have diabetes)
• to treat your heart when it cannot pump enough blood to the rest of your body (heart failure)
• as treatment following heart attack (myocardial infarction) complicated with heart failure.

2. What you need to know before you take RAMIPRES tablets

Do not take RAMIPRES tablets if:

• you are allergic to ramipril, any other ACE inhibitor medicine or any of the ingredients of this medicine. Signs of an allergic reaction may include a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue
• you have ever had a serious allergic reaction called “angioedema”. The signs include itching, hives (urticaria), red marks on the hands, feet and throat, swelling of the throat and tongue, swelling around the eyes and lips, difficulty breathing and swallowing
• you have taken or are currently taking sacubitril/ valsartan, a medicine used to treat a type of long term (chronic) heart failure in adults
• you are having dialysis or any other type of blood filtration. Depending on the machine that is used, RAMIPRES tablets may not be suitable for you
• you have kidney problems where the blood supply to your kidney is reduced (renal artery stenosis)
• you are in the last 6 months of pregnancy (see section below on “Pregnancy and breast-feeding”)
• your blood pressure is abnormally low or unstable. Your doctor will need to make this assessment.
• you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren

Do not take RAMIPRES tablets if any of the above apply to you. If you are not sure, talk to your doctor before taking RAMIPRES tablets.

Warnings and precautions

Talk to your doctor or pharmacist before taking RAMIPRE tablets if you:

• have heart, liver or kidney problems
• have lost a lot of body salts or fluids (through being sick (vomiting), having diarrhoea, sweating more than usual, being on a low salt diet, taking diuretics (water tablets) for a long time or having had dialysis)
• are going to have treatment to reduce your allergy to bee or wasp stings (desensitisation)
• are going to receive an anaesthetic. This may be given for an operation or any dental work. You may need to stop your RAMIPRES tablets treatment one day beforehand; ask your doctor for advice
• have high amounts of potassium in your blood (shown in blood test results)
• you are taking medicines or have conditions which may decrease sodium levels in your blood. Your doctor may carry out regular blood tests, particularly for checking the levels of sodium in your blood, especially if you are elderly.
• are taking medicines that may increase the risk of angioedema, a serious allergic reaction, such as mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus), vildagliptin, neprilysin (NEP) inhibitors (such as racecadontril) or sacubitril/valsartan. For sacubitril/valsartan, see section 2 “Do not take RAMIPRES tablets”.
• have collagen vascular disease such as scleroderma or systemic lupus erythematosus
• think that you are (or might become) pregnant. RAMIPRES tablets are not recommended in the first 3 months of pregnancy and may cause serious harm to your baby after 3 months of pregnancy, see section “Pregnancy and breast-feeding”.
• are taking any of the following medicines used to treat high blood pressure:
  • An angiotensin II receptor blocker (ARBs) (also known as sartans – for example valsartan, telmisartan, irbesartan), in particular if you have diabetes-related kidney problems.
  • Aliskiren

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

Children

RAMIPRES tablets are not recommended for use in children and adolescents below 18 years of age because the safety and efficacy of RAMIPRES tablets in children has not yet been established.

If any of the above apply to you (or you are not sure), talk to your doctor before taking RAMIPRES tablets.

Other medicines and RAMIPRES tablets

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. This is because RAMIPRES tablets can affect the way some other medicines work. Also some medicines can affect the way RAMIPRES tablets work.

Tell your doctor if you are taking any of the following medicines. They can make RAMIPRES tablets work less well:

• medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen or indometacin and aspirin)
• medicines used for the treatment of low blood pressure, shock, cardiac failure, asthma or allergies such as ephedrine, noradrenaline or adrenaline.

Your doctor will need to check your blood pressure.

• Tell your doctor if you are taking any of the following medicines. They can increase the chance of getting side effects if you take them with RAMIPRES tablets:
• sacubitril/valsartan – used for treating a type of long term (chronic) heart failure in adults (see section 2 ‘Do not take RAMIPRES tablets’)
• medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen or indometacin and aspirin)
• medicines for cancer (chemotherapy)
• medicines to stop the rejection of organs after a transplant such as ciclosporin
• diuretics (water tablets) such as furosemide
• medicines which can increase the amount of potassium in your blood such as spironolactone, triamterene, amiloride, potassium salts, trimethoprim alone or in combination with sulfamethoxazole (for infections) and heparin (for thinning blood)
• steroid medicines for inflammation such as prednisolone
• allopurinol (used to lower the uric acid in your blood)
• procainamide (for heart rhythm problems)
• temsirolimus (for cancer)
• sirolimus, everolimus (for prevention of graft rejection)
• vildagliptin (used for treating type 2 diabetes)
• racecadotril (used against diarrhoea)
• your doctor may need to change your dose and/ or to take other precautions if you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings “Do not take RAMIPRES tablets” and “Warnings and precautions”).

Please tell your doctor if you are taking any of the following medicines. They may be affected by RAMIPRES tablets:

• medicines for diabetes such as oral glucose lowering medicines and insulin. RAMIPRES tablets may lower your blood sugar amounts. Check your blood sugar amounts closely while taking RAMIPRES tablets
• lithium (for mental health problems). RAMIPRES tablets may increase the amount of lithium in your blood. Your lithium amount will need to be closely checked by your doctor.

Your doctor may need to change your dose and/or to take other precautions:

If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings ‘Do not take RAMIPRES tablets’ and ‘Warnings and precautions’)

If any of the above apply to you (or you are not sure), talk to your doctor before taking RAMIPRES tablets.

RAMIPRES tablets with food and alcohol

Drinking alcohol with RAMIPRES tablets may make you feel dizzy or light-headed. If you are concerned about how much you can drink while you are taking RAMIPRES tablets, discuss this with your doctor as medicines used to reduce blood pressure and alcohol can have additive effects. RAMIPRES tablets may be taken with or without food.

Pregnancy and breast-feeding

You must tell your doctor if you think that you are (or might become) pregnant.

You should not take RAMIPRES tablets in the first 12 weeks of pregnancy, and you must not take them at all after the 13th week as their use during pregnancy may possibly be harmful to the baby. If you become pregnant while on RAMIPRES tablets, tell your doctor immediately. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

You should not take RAMIPRES tablets if you are breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Driving and using Machines

You may feel dizzy while taking RAMIPRES tablets. This is more likely to happen when you start taking RAMIPRES tablets or start taking a higher dose. If this happens, do not drive or use any tools or machines.

RAMIPRES tablets contain lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take RAMIPRES tablets

Always take this medicine exactly as described in this leaflet or as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Take this medicine by mouth at the same time of the day each day. Swallow the tablets with liquid.

Doses:

• Treatment of high blood pressure

The usual starting dose is 1.25mg or 2.5mg once daily. Your doctor will adjust the amount you take until your blood pressure is controlled. The maximum dose is 10mg once daily. If you are already taking diuretics (water tablets), your doctor may stop or reduce the amount of the diuretic you take before beginning treatment with RAMIPRES tablets.

• Treatment to reduce or delay the worsening of kidney problems

You may be started on a dose of 1.25mg or 2.5mg once daily. Your doctor will adjust the amount you are taking. The usual dose is 5mg or 10mg once daily.

• Treatment of heart failure

The usual starting dose is 1.25mg once daily.

Your doctor will adjust the amount you take.

The maximum dose is 10mg daily.

Two administrations per day are preferable.

• Treatment after you have had a heart attack

The usual starting dose is 1.25mg once daily to 2.5mg twice daily. Your doctor will adjust the amount you take. The usual dose is 10mg daily.

Two administrations per day are preferable.

• Elderly

Your doctor will reduce the initial dose and adjust your treatment more slowly.

If you take more RAMIPRES tablets than you should

Symptoms associated with overdose may include abnormally slow heart action and renal failure.

Tell a doctor or go to the nearest hospital casualty department straight away. Do not drive to the hospital, get somebody else to take you or call for an ambulance. Take the medicine pack with you.

This is so the doctor knows what you have taken.

If you forget to take RAMIPRES tablets

If you miss a dose, take your normal dose when it is next due. Do not take a double dose to make up for a forgotten tablet.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.  Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking RAMIPRES tablets and contact your doctor immediately, if you notice any of the following serious side effects - you may need urgent medical treatment:

• Swelling of the face, lips or throat which makes it difficult to swallow or breathe, as well as itching and rashes. This could be a sign of a severe allergic reaction to RAMIPRES tablets.
• Severe skin reactions including rash, ulcers in your mouth, worsening of a pre-existing skin disease, reddening, blistering or detachment of skin (such as Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme).

Contact your doctor immediately, if you notice any of the following:

• Faster heart rate, uneven or forceful heartbeat (palpitations), chest pain, tightness in your chest or more serious problems including heart attack and stroke
• Shortness of breath or a cough. These could be signs of lung problems
• Bruising more easily, bleeding for longer than normal, any sign of bleeding (e.g. bleeding from the gums), purple spots blotching on the skin or getting infections more easily than usual, sore throat and fever, feeling tired, faint, dizzy or having pale skin. These can be signs of blood or bone marrow problems
• Severe stomach pain which may reach through to your back. This could be a sign of pancreatitis (inflammation of the pancreas).
• Fever, chills, tiredness, loss of appetite, stomach pain, feeling sick, yellowing of your skin or eyes (jaundice). These can be signs of liver problems such as hepatitis (inflammation of the liver) or liver damage.

Tell your doctor if you notice any of the following side effects or they get worse:

Common (may affect up to 1 in 10 people)

• Headache or feeling tired
• Feeling dizzy. This is more likely to happen when you start taking RAMIPRES tablets or start taking a higher dose
• Fainting, hypotension (abnormally low blood pressure), especially when you stand or sit up quickly
• Dry tickly cough, inflammation of your sinuses

• (sinusitis) or bronchitis, shortness of breath
• Stomach or gut pain, diarrhoea, indigestion,
• feeling or being sick
• Skin rash with or without raised area
• Chest pain
• Cramps or pain in your muscles
• Blood tests showing more potassium than usual in your blood.

Uncommon (may affect up to 1 in 100 people)

• Balance problems (vertigo)
• Itching and unusual skin sensations such as numbness, tingling, prickling, burning or creeping on your skin (paraesthesia)
• Loss or change in the way things taste
• Sleep problems
• Feeling depressed, anxious, more nervous than usual or restless
• Blocked nose, difficulty breathing or worsening of asthma
• A swelling in your gut called “intestinal angioedema” presenting with symptoms like abdominal pain, vomiting and diarrhoea
• Heartburn, constipation or dry mouth
• Passing more water (urine) than usual over the day
• Sweating more than usual
• Loss or decrease of appetite (anorexia)
• Increased or irregular heartbeats
• Swollen arms and legs. This may be a sign of your body holding onto more water than usual
• Flushing
• Blurred vision
• Pain in your joints
• Fever
• Sexual inability in men, reduced sexual desire in men or women
• An increased number of certain white blood cells (eosinophilia) found during a blood test
• Blood tests showing changes in the way your liver, pancreas or kidneys are working.

Rare (may affect up to 1 in 1,000 people)

• Feeling shaky or confused
• Red and swollen tongue
• Severe flaking or peeling of the skin, itchy, lumpy rash
• Nail problem (e.g. loosening or separation of a nail from its bed)
• Skin rash or bruising
• Blotches on your skin and cold extremities
• Red, itchy, swollen or watery eyes
• Disturbed hearing and ringing in your ears
• Feeling weak
• Blood tests showing a decrease in the number of red blood cells, white blood cells or platelets or in the amount of haemoglobin.

Very rare (may affect up to 1 in 10,000 people)

• Being more sensitive to the sun than usual.

Other side effects reported:

Please tell your doctor if any of the following gets serious or lasts longer than a few days.

• Difficulty concentrating
• Swollen mouth
• Blood tests showing too few blood cells in your blood
• Blood tests showing less sodium than usual in your blood
• Fingers and toes changing colour when you are cold and then tingling or feeling painful when you warm up (Raynaud’s phenomenon)
• Breast enlargement in men
• Slowed or impaired reactions
• Burning sensation
• Change in the way things smell
• Hair loss.

Frequency not known: concentrated urine (dark in colour), feel or are sick, have muscle cramps, confusion and fits which may be due to inappropriate ADH (anti-diuretic hormone) secretion. If you have these symptoms contact your doctor as soon as possible.

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

5. How to store RAMIPRES tablets

• Keep this medicine out of the sight and reach of children.
• Store below 25°C.
• Do not use this medicine after the expiry date which is stated on the carton and the blister or the tablet container.
• The expiry date refers to the last day of that month.

6. Contents of the pack and other information

What RAMIPRES tablets contain

The active substance is ramipril.

Each tablet contains either 1.25mg, 2.5mg, 5mg or 10mg of the active ingredient.

The other ingredients are:

Hydroxy propyl methyl cellulose

Microcrystalline cellulose

Pregelatinized starch

Maize Starch

Colloidal anhydrous silica

Sodium stearyl fumarate

Ferric oxide (Yellow)

Details of Manufacturers

Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai, Maharashtra, INDIA

Details of Permission or Licence Number with Date

MNB/05/109      4/4/2015

Date of Revision

Last Updated: 27/8/2021